Hepatitis C virus (HCV) is an important human pathogen that can cause acute and chronic hepatitis, liver cirrhosis and, possibly, hepatocellular carcinoma. This virus accounts for up to 25% of community- acquired hepatitis and over 90% of transfusion-associated hepatitis in the United States. The virus particles contain a positive polarity, single-stranded RNA genome with 5' and 3' noncoding (NC) regions. The core (C), envelope 1 (E1) and envelope 2 (E2) proteins are encoded at the 5' terminus and the nonstructural proteins are encoded at the 3' terminus of the single open reading frame of the genome. Furthermore, the finding of genetic heterogeneity of the HCV genome, especially in the genes encoding the envelope proteins, suggests that there may be heterogeneity similar to that seen in the envelope gene of human immunodeficiency viruses. Such a finding would bode ill for attempts at vaccine development. In this project we have extended our previous sequence analysis of the viral genome to include the core gene, which is the most conserved HCV gene. The phylogenetic analysis of this gene was in agreement with that of the envelope 1 gene, which is highly variable. Additional analysis identified conserved features of the core gene that will be useful in understanding the role of the nucleocapsid protein in viral replication. Other major findings were: (i) identification of HCV RNA in dialysis patients; (ii) prevention of HCV infection in chimpanzees following antibody-mediated neutralization in vitro; and (iii) establishment and characterization of antibody-free prototype strains of the different genotypes of HCV.